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NM_000218.3(KCNQ1):c.932C>T (p.Thr311Ile) AND Long QT syndrome 1

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Aug 1, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003319314.2

Allele description [Variation Report for NM_000218.3(KCNQ1):c.932C>T (p.Thr311Ile)]

NM_000218.3(KCNQ1):c.932C>T (p.Thr311Ile)

Gene:
KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p15.5
Genomic location:
Preferred name:
NM_000218.3(KCNQ1):c.932C>T (p.Thr311Ile)
HGVS:
  • NC_000011.10:g.2583445C>T
  • NG_008935.1:g.143455C>T
  • NM_000218.3:c.932C>TMANE SELECT
  • NM_001406836.1:c.932C>T
  • NM_001406837.1:c.662C>T
  • NM_001406838.1:c.488C>T
  • NM_181798.2:c.551C>T
  • NP_000209.2:p.Thr311Ile
  • NP_000209.2:p.Thr311Ile
  • NP_001393765.1:p.Thr311Ile
  • NP_001393766.1:p.Thr221Ile
  • NP_001393767.1:p.Thr163Ile
  • NP_861463.1:p.Thr184Ile
  • NP_861463.1:p.Thr184Ile
  • LRG_287t1:c.932C>T
  • LRG_287t2:c.551C>T
  • LRG_287:g.143455C>T
  • LRG_287p1:p.Thr311Ile
  • LRG_287p2:p.Thr184Ile
  • NC_000011.9:g.2604675C>T
  • NM_000218.2:c.932C>T
  • NM_181798.1:c.551C>T
  • NR_040711.2:n.825C>T
  • P51787:p.Thr311Ile
Protein change:
T163I
Links:
UniProtKB: P51787#VAR_009927; dbSNP: rs199472746
NCBI 1000 Genomes Browser:
rs199472746
Molecular consequence:
  • NM_000218.3:c.932C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.932C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.662C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406838.1:c.488C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.551C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome 1 (LQT1)
Identifiers:
MONDO: MONDO:0100316; MedGen: C4551647; Orphanet: 101016; Orphanet: 768; OMIM: 192500

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004024203Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Aug 1, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005399461Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Feb 2, 2022) 		germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular genetics of the long QT syndrome: two novel mutations of the KVLQT1 gene and phenotypic expression of the mutant gene in a large kindred.

Saarinen K, Swan H, Kainulainen K, Toivonen L, Viitasalo M, Kontula K.

Hum Mutat. 1998;11(2):158-65.

PubMed [citation]
PMID:
9482580

Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.

Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT.

Circulation. 2000 Sep 5;102(10):1178-85.

PubMed [citation]
PMID:
10973849
See all PubMed Citations (10)

Details of each submission

From Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes, SCV004024203.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005399461.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional ion transporter domain (pore) (DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These alternative changes (p.(Thr311Ala, p.(Thr311Leu)) have been reported in at least two individuals with long QT syndrome (LQTS) (LOVD, PMID: 20541041, PMID: 15733182). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been observed in at least two unrelated individuals with LQTS (LOVD, PMID: 9482580, PMID: 10973849, PMID: 14678125). (SP) 0903 - This variant has limited evidence for segregation with disease, where it was found in three affected relatives with LQTS (PMID: 9482580). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Whole cell patch clamp studies of transfected CHO cells have demonstrated impaired current. However, the biological significance of this study is uncertain (PMID: 25705178). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 25, 2025